Heteroaromatics

Question 1

Show the enol and enolate form of a carbonyl.

Answer 1

Question 2

Draw the formation of an imine from a carbonyl.

Answer 2

Question 3

Draw the aldol and mannich reactions. (enol Nu)

Answer 3

Question 4

Draw and describe the conditions of a Michael reaction.

Answer 4

Question 5

Draw the general mechanism of the Friedel-Crafts reaction.

Answer 5

Question 6

What are the methods of producing 1,3, 1,4 and 1,5 dicarbonyls?

Answer 6

1,3: Enolate and electrophilic carbonyl with LG

1,4: Enolate and carbonyl with an α-bromine LG

1,5: Michael reaction with soft carbonyl nucleophile

Question 7

Draw the following molecules: pyridine, pyrrole, furan and thiophene.

Answer 7

Question 8

Draw the following molecules: imidazole, oxazole, thiazole, quinoline, isoquinoline and indole.

Answer 8

Question 9

What are the differences between benzene and pyridine?

Answer 9

The electronegativity of the nitrogen makes the ring inductively π-defficient compared to benzene. This deshields the hydrogen closest to the N.

The lone pair of N points out of the ring so it acts as a nucleophile and a weak base.

Question 10

How can pyridine be used for esterification reactions with an acid chloride? Why is this useful?

Answer 10

The pyridine substitutes at a carbonyl, removing a chloride. Pyridine then acts as a leaving group when an alcohol attacks the carbonyl. The pyridine then acts as a base and cleans up the HCl produced.

Question 11

Describe how pyridines undergo electrophilic aromatic substitution. Draw relevant mechanisms.

Answer 11

Pyridines by themselves are not good at electrophilic aromatic substitution as: electrophiles react at N, the ring is π defficient and the N destabilises the intermediate.

However a pyridine N-oxide, where the pyridine is bonded to an O^-, can undergo a substitution. The oxygen adds electron density, making the pyridine nucleophilic.

Question 12

For pyridine, explain where nucleophilic aromatic substitution will occur.

Answer 12

At C2 or C4 but not C3 beacause it doesn’t have a resonance form with the negative charge on the nitrogen. This is analogous to enones (carbonyl and alkene).

Question 13

What is the Chinchibabin substitution reaction? Draw the mechanism and give possible reagents of varying strengths.

Answer 13

This is also possible with organolithiums and Grignards. The reaction can also occur with weaker nucleophiles if a better LG is present such as Cl^-.

Question 14

How can nucleophilic aromatic substutions occur using pyridine N-oxides? Draw the mechanism. What is the driving force of the reaction?

Answer 14

PO₂Cl is a very good leaving group and it is very favourable to form the oxygen double bond.

Question 15

What is notable about the reactivity of 2 and 4-methyl pyridines?

Answer 15

They undergo elimination of a methyl hydrogen using LDA to form a double bond off the ring and a negative charge on the nitrogen. This can then react as a nucleophile, similar to how a enolate would react.

Question 16

Describe the basic RSA of pyridines and draw how they can be synthesised.

Answer 16

The pyridine contains groups that appear to look like an enamine and an imine. Therefore they can be synthesised from a 1,5-dicarbonyl and an amine which is in turn synthesised from a carbonyl Michael reaction.

Question 17

Draw a mechanism for the Hantzch synthesis and give a summery of the basic steps.

Answer 17

Form an imine from one carbonyl, the other two carbonyls undergo an aldol reaction which is then attacked by the imine, which then ring closes.

Question 18

Describe the structure of pyrrole.

Answer 18

The 5 atom ring has a nitrogen with its lone pair delocalised into the ring giving it the same number of π electrons as benzene. This makes the ring π-excessive (greater electron density than benzene) which is reflected in lower chemical shifts.

Question 19

What strength base can deprotonate pyrrole?

Answer 19

Only strong bases such as NaH since the hydrogens are all orthogonal to the delocalised p orbitals.

Question 20

How and where does pyrrole react with electrophiles?

Answer 20

It reacts at C2 by aromatic substitution since this gives the ring the most resonance structures. This reaction is fast since the ring is π-excessive meaning activating agents aren’t as important.

Question 21

Draw the mechanism of the Vilsmeier formylation with pyrrole to introduce a COR group.

Answer 21

Question 22

How can the Mannich reaction be used to add poor nucleophiles onto a pyrrole? Draw the mechanism.

Answer 22

Question 23

How can pyrroles be made into good nucleophiles? How does this compare for furan and thiophene?

Answer 23

A strong base can deprotonate at the nitrogen which is then reacted with an electrophile such as MeI to form the substituted nitrogen.

BuLi can then be used to deprotonate at C2 (C2 is favoured due to nitrogen -I effects) which can then react with various electrophiles.

For furan and thiophene the same proccess can occur, except the heteroatom doesn’t need deprotonating first.

Question 24

Describe how pyrrole can be anaylsed to construct a synthesis. Draw the mechanism of the Hantzch synthesis.

Answer 24

There is an enamine type group so the cyclisation can occur from a 1,4-carbonyl-imine where the iminium attacks the carbonyl. The 1,4 structure is formed from a substitution at the alpha carbonyl position.

Question 25

Give the synthesis of pyrrole to form the substituted nitrogen directly.

Answer 25

Question 26

Draw a mechanism for the synthesis of pyrrole without using a 1,4-dicarbonyl or equivalent.

Answer 26

Question 27

Explain the differences in reactivity between pyrrole, furan and thiophene?

Answer 27

Furan and thiophene are less nucleophilic than pyrrole since S has worse overlap with the carbon aromatic orbitals and O is more electronegative than N.

Order of reactivity towards electrophilic aromatic substitution:

pyrrole > furan > thiophene >> benzene >> pyridine

π excessive - normal - π defficient

Question 28

What may happen to furan instead of electrophilic aromatic substitution depending on conditions which would not happen to pyrrole? Explain the proccess and how it occurs.

What implications does this have for other proccesses?

Answer 28

Instead of substituion/elimation of a hydrogen, a solvent such as MeOH may act as a nucleophile and add to the molecule meaning overall an addition has occured and furan has acted as a diene. This can occur since furan has the lowest aromatic stability so the driving force to eliminate the H is lower.

Furan may also be able to undergo other diene reactions like diels-alder to form a 6 membered ring.

Question 29

Draw the mechanism for the synthesis of furan. How does this compare to the synthesis of thiophene?

Answer 29

Thiophene has the same synthesis except the dithiocarbonyl is used which is made from the dicarbonyl and P₂S₅.

Question 30

Describe the structural features and reactivity of the 1,3-azoles.

Answer 30

Each one is pyrrole, furan and thiophene with a nitrogen at the 3 position. The nitrogen always points out of the plane of the aromaticity. Imidazole can act as a base readily but the others have a much smaller pKa.

Question 31

Can 1,3-azoles react via electrophilic aromatic substituiton?

Answer 31

The 3-N deactivates the reactivity to electrophilic aromatic substitution in the same way as pyridine (tendancy to react at the N, electron deficiency, destabilisation of the intermediate). However it can be reactivated by a electron-donating group (such as NMe₂) at C2 (opposite side to N) which allows C3 to act as the nucleophile.

Question 32

Where does deprotonation of 1,3-azoles occur, why is this location favoured and what strength base is required? What is the prerequisite for this too occur in 1,3-imidazole?

Answer 32

At the C2 position between the heteroatoms due to their electron withdrawing nature. A strong base such as BuLi is required. For 1,3-imidazole nitrogen with a hydrogen must be protected.

Question 33

How can C2 alkyl groups on 1,3-azoles be used?

Answer 33

They can be deprotontated using BuLi and used as an enolate equivalent as the N can stablilse the negative charge.

Question 34

Outline a synthesis for 1,3-azoles that can be used to make imidazole and thiazole. Give the mechanism.

Answer 34

An alpha substituted ketone is reacted with a carboxylilic acid derivative. This is normally an alpha-bromoketone with an amide where the carbonyl is whichever heteroatom you want. The heteroatom then substitutes at the bromine and the nitrogen reacts at the carbonyl forming the imine.

Question 35

Outline the synthesis and draw the mechanism for oxazole and describe why it cannot be synthesised the same way as the other 1,3-azoles.

Answer 35

The amide is not nucleophilic enough to react with the bromoketone since it has conjugated groups so the amine needs to be on the ketone and the LG needs to be on the carboxylic acid derivative.

Question 36

Describe the structure and basic reactivity of quinoline and isoquinoline.

Answer 36

Quinoline is a pyridine ring fused with a benzene ring at C2 and C3. Isoquinoline is the same but fused at C3 and C4. The pyridine reacts as a pyridine would do, as does the benzene.

Question 37

For quinoline and isoquinoline, where does electrophilic aromatic substitution occur? Draw the resonance structures.

Answer 37

The nitrogen deactivates the pyridine so the reaction occurs on the benzene. On quinoline the carbons that react do not disrupt the aromaticity of the pyridine (the carbons closest to the ring attach to the electrophile).

Question 38

For quinoline and isoquinoline, where does nucleophilic aromatic substitution occur? Give some possible reagents.

Answer 38

As in benzene, the π electrons block nucleophiles from the carbocyclic ring but as pyridine is π deficient, it can occur on the heterocycle. For quinoline, the substitution occurs at the 2 and 4 postitions (given N is 1) like pyridine due to the N stabilisation. For isoquinoline, the reactions also occur at both 2 positions but there is no 4 postition that wouldn’t interfere with carbocyclic aromaticity.

Reagents are the same as the ones for pyridine which include: NH₂Na or organometallic nucleophile and H^- LG, RO^- nucleophile and Cl^- LG and N-oxide reactions with poor nucleophiles.

Question 39

What is the notable reactivity of 2 and 4-methyl quinolines and 1-methyl isoquinolines?

Answer 39

They can be deprotonated at the methyl by LDA to form the alkene and the negative charge on the nitrogen. They then mirror enolate reactivity.

Question 40

How do you synthesis quinoline? Give the basic steps and the mechanism.

Answer 40

RSA of quinoline leads to a phenylamine and a 1,3 dicarbonyl. The imine forms at one carbonyl, then the aromaticity breaks to form the heterocycle which then reforms.

Question 41

Draw the mechanism of the synthesis of quinoline from a michael acceptor.

Answer 41

Question 42

Outline and draw the mechanism for an isoquinoline synthesis.

Answer 42

The imine functionalilty can be broken down to an aromatic carbonyl and an amine with a protected carbonyl. Once the amine has reacted the carbonyl can be deprotected and reacted with the carbocyclic ring.

Question 43

What alternative method can be used to produce isoquinoline using POCl₃? Draw the mechanism.

Answer 43

Question 44

Give the properties, reactivity towards electrophilic aromatic substitution and nucleophilic potential of indoles. Draw the mechanisms of the possible substitutions.

Answer 44

An indole is a benzene ring fused with a pyrrole ring making it π-excessive. The high electron density makes electrophilic aromatic substitution favourable at the C3 postion (opposite side of the N on the indole) as C2 disrupts the benzene. The indole N-H can be deprotonated with NaH, then reactions with electrophiles can occur at either C3 for soft electrophiles, and the N^- for hard electrophiles. When the nitrogen is blocked the C2 position is deprotonated.

Question 45

Outline and draw the mechanism of a simple indole synthesis.

Answer 45

Disconnection of the enamine to give an aminal allows you to synthesis indole from an aromatic amide and a deprotonated methyl group on the aromatic ring.

Question 46

Give the Fischer Indole synthesis overview and mechanism.

Answer 46

Using an aromatic hydrazine (Ph-NHNH₂) and a pent-3-one, the enamine forms which attacks then benzene while breaking the N-N bond. The aromatic amine then kicks out the other amine.